The proposed studies investigate the individual and combined use of established and new antiviral agents in ocular and other herpetic disease. The goal of the proposed study is to reduce toxicity while enhancing or maintaining the antiviral activity of established potent antiviral agents. Toward this end, we will utilize the following agents in lower than usual dose (1) 5-iodo-2'deoxyuridine (IDU) and (2) 9beta-D-arabinofuranosyladenine (Ara A), or new potent antiviral agent (3) 3',5'-di-o-acetyl-5-iodo-2'-deoxyuridine (Ac2 IDU) in lower than usual doses. Each of these drugs will be studied in combination with one of the following antiviral agents: (1) 5'-amino-5'-deoxythymidine (ATdR), (2) 5-iodo-5'-amino-2',5'-dideoxyuridine (AIU) and (3) 9-(2-hydroxyethoxymethyl) guanine (Acyclovir, ACV) which are relatively non-toxic. These combinations will be used to treat experimental models of herpes simplex virus (HSV), ocular infection, trigeminal ganglionic latency, encephalitis, cutaneous disease and HSV-induced malignant tumors. In an additional series of studies, the new antiviral thymidine analogs, (1) 5'-amino-3'-hexanoyl-5'-deoxythymidine (AHdT), (2) 5'-amino-3'-valeryl-5'-deoxythymidine (AVdT) and (3) 3',5'-di-o-valeryl-2'-deoxy-5-todouridine (Va2IUdR), compounds developed in the same laboratory where IDU was conceived and synthesized, and a psychotrophic drug with significant antiherpes activity, benzoctamine HC1, will be evaluated for therapeutic efficacy in various animal and in vitro HSV models. The effect of single or combined antivirals on acute infection and established latent HSV infection in trigeminal ganglia will be compared to that of ACV. The latter drug has shown good therapeutic efficacy in preventing establishment of latent HSV in the sensory ganglia of laboratory animals. These studies will be aimed toward the ultimate control of ganglionic viral reactivation and, therefore, prevention of recurrent end organ disease. Toxicologic and teratologic studies of the above single or combined antivirals will be carried out to evaluate the safety of these antiviral agents as topical or systemic agents. Through the abive studies we expect to obtain significant information on new approaches to the use of established and recently synthesized antiviral drugs while minimizing toxic side effects in therapy of ocular, ganglionic, malignant and other herpetic infections.